CN104163815B - 含吲哚的喹唑啉类化合物及其在治疗egfr依赖性肿瘤疾病中的用途 - Google Patents
含吲哚的喹唑啉类化合物及其在治疗egfr依赖性肿瘤疾病中的用途 Download PDFInfo
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- CN104163815B CN104163815B CN201310193297.3A CN201310193297A CN104163815B CN 104163815 B CN104163815 B CN 104163815B CN 201310193297 A CN201310193297 A CN 201310193297A CN 104163815 B CN104163815 B CN 104163815B
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- quinazoline
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明提供了一系列有良好治疗活性的含吲哚的喹唑啉类化合物。另外,本发明还提供了含有这些化合物的药物组合物、这些化合物的制备方法以及这些化合物在制备抗肿瘤药物中的用途等。
Description
技术领域
本发明属于药物化学领域,具体而言,本发明涉及一系列有良好治疗活性的含吲哚的喹唑啉类化合物。另外,本发明还涉及含有这些化合物的药物组合物、这些化合物的制备方法以及这些化合物在制备抗肿瘤药物中的用途等。
背景技术
癌症是人类健康的主要威胁之一,大多数肿瘤都与外界环境因素相关,全世界每年有500万人以上死于癌症。虽然现在己有一些治疗办法,如外科手术、放疗、化疗等可使患者治愈,但治愈率不高。目前,使用化学药物预防及治疗是克服肿瘤的最有效方法之一。
表皮生长因子受体(EGFR)是一种广泛分布于人体各组织细胞上的多功能跨膜糖蛋白,属于ErbB家族成员之一,其与HER2(ErbB2)、HER3(ErbB3)及HER4(ErbB4)共同组成ErbB大家族。它们具有一定的同源结构,同属于受体酪氨酸激酶。肿瘤临床研究中发现,己知70%的恶性肿瘤都会出现一种或几种ErbB受体的过表达现象。在肺癌、乳腺癌、膀胱癌、卵巢癌、前列腺癌等多种肿瘤细胞中发现EGFR的表达量超过正常细胞水平的100倍。介于表皮生长因子受体介导的信号传导通路在肿瘤细胞的形成、发展、增殖和生存方面起着至关重要的作用,因此,EGFR一直是抗肿瘤药物的一个重要靶标。目前为止,体内外的试验和临床研究显示,作为一种有前景的抗肿瘤药物,EGFR小分子酪氨酸激酶抑制剂无论是单独应用还是同化放疗联合使用,都表现出显著的抗肿瘤作用。已经上市的抗肿瘤药物如吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等属于第一代EGFR小分子抑制剂。临床实践中发现,肿瘤患者对第一代EGFR小分子抑制剂的敏感性较低,仅有约10%的北美患者和约20%的亚洲患者对它们有响应。然而,随着治疗时间的延长,大部分患者会出现获得性耐药。研究表明有超过50%的获得性耐药患者在EGFR上检测到了继发突变T790M。而且最初T790M突变只在TKI获得性耐药的患者中被检测到,但随后在未经任何治疗的患者中也被检测到。
目前,EGFR抑制剂的构效关系并不明朗,有的结构差别很小的化合物,其针对EGFR抑制的效果却相差很大。本发明人经过艰苦努力,令人意外地设计并合成出一系列新的含吲哚的喹唑啉类化合物,其具有优良的EGFR抑制效果,不可逆地抑制EGFR及细胞有丝分裂的各种途径,从而用于治疗肿瘤疾病。
发明内容
本发明要解决的技术问题在于提供新的含吲哚的4-氨基喹唑啉类化合物和/或提供其在治疗或预防肿瘤(尤其是EGFR依赖性肿瘤)方面的新用途。
具体而言,在第一方面,本发明提供了含吲哚的喹唑啉类化合物,所述化合物选自:
N4-(1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-甲基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-丙基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-烯丙基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-(3-氟苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-(3-氯苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(2-甲基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(2-叔丁基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
5-((6-氨基喹唑啉-4-芳基)氨基)-1H-吲哚-2-羧酸乙酯;
5-((6-氨基喹唑啉-4-芳基)氨基)-1H-吲哚-2-羧酸;
5-((6-氨基喹唑啉-4-芳基)氨基)-N-丙基-1H-吲哚-2-酰胺;
5-((6-氨基喹唑啉-4-芳基)氨基)-N-叔丁基-1H-吲哚-2-酰胺;
N4-(3-溴-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;
N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰氯;
N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;
N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺;
N-(4-((1-(3-氯苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺;N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;和
N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)-3-氯丙酰胺。
优选本发明第一方面的化合物选自:
N4-(1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-(3-氟苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(1-(3-氯苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N4-(3-溴-1H-吲哚-5-芳基)喹唑啉-4,6-二胺;
N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;
N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰氯;
N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;
N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺;
N-(4-((1-(3-氯苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺;
N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺;和
N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)-3-氯丙酰胺。
也优选本发明第一方面还提供上述化合物的互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐。其中,优选溶剂化物是水合物。其中,术语“药学上可接受的盐”是本领域技术人员所熟知的,在本发明中,优选其指的是本发明第一方面的化合物与酸形成的符合药用安全标准且不影响活性化合物发挥药效的加成盐。其中,酸可以是机酸酸,也可以是无机酸。常用的酸可以选自氢溴酸、盐酸、硫酸、亚硫酸、乙酸、草酸、戊酸、油酸、棕榈酸、硬脂酸、月桂酸、硼酸、苯甲酸、乳酸、磷酸、甲苯甲酸、柠檬酸、马来酸、富马酸、琥珀酸、酒石酸、苯甲酸、甲磺酸、葡萄糖酸、乳糖酸和月桂基磺酸。药学上可接受的盐可以在合成了化合物之后与相应的无机或有机酸反应而制成,优选在合成化合物的过程最后步骤(如,分离和提纯化合物)中原位制备。
在第二方面,本发明提供了用于治疗或预防肿瘤的药物组合物,其包含本发明第一方面的化合物或其互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐,并且其还包含药学上可接受的辅料。其中,术语“药学上可接受的辅料”是本领域技术人员所熟知的,包括药学上可接受的载体、赋形剂、稀释剂等,它们与活性成分相容。运用药学上可接受的辅剂制备药物组合物,可以采用本领域普通技术人员公知的技术来进行。本发明的药物组合物可以是将本发明第一方面的化合物和药学上可接受的辅剂组合在一起而配制成的各种制剂,优选为固体制剂和液体制剂。本发明的制剂可以为单位剂量形式,如片剂、丸剂、胶囊(包括持续释放或延迟释释放形式)、粉剂、混悬剂、颗粒剂、酊剂、糖浆剂、乳液剂、悬浮液、针剂、等剂型以及各种缓释剂型,从而适合各种给药方式,例如口服、非肠道注射、粘膜、肌肉、静脉内、皮下、眼内、皮内或经过皮肤等的给药形式。
优选本发明第二方面的药物组合物中,肿瘤是EGFR依赖性肿瘤,即由ErbB激酶介导而细胞癌化的肿瘤。
也或更优选本发明第二方面的药物组合物中,肿瘤是肺癌、乳腺癌、肠癌、卵巢癌、肾癌、膀胱癌、口腔癌、喉癌、食道癌、胃癌或头颈癌。
在第三方面,本发明提供了本发明第一方面的化合物或其互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐在制备用于治疗或预防肿瘤的药物中的应用。
优选本发明第三方面的应用中,肿瘤是EGFR依赖性肿瘤,即由ErbB激酶介导而细胞癌化的肿瘤。
也或更优选本发明第三方面的应用中,肿瘤是肺癌、乳腺癌、肠癌、卵巢癌、肾癌、膀胱癌、口腔癌、喉癌、食道癌、胃癌或头颈癌。
在第四方面,本发明提供了本发明第一方面的化合物或其互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐在制备用于抑制EGFR、HER2、HER3和/或HER4过度表达或异常激活的细胞增殖的药品或试剂中的应用。
在本文中,如无相反指示,术语“试剂”指的是达不到药用标准的试剂,如实验室研究所用的试剂。
在第五方面,本发明提供了本发明第一方面的化合物或其互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐在制备用于特异性或广谱性抑制EGFR激酶的药品或试剂中的应用。
优选本发明第五方面的应用中,EGFR激酶是野生型或耐药突变的EGFR激酶。为了定义清楚起见,术语“特异性抑制”指的是仅能针对两种或两种以下的EGFR激酶具有IC50小于100nM的抑制率;术语“广谱性抑制”指的是针对两种以上(如三种或四种)的EGFR激酶具有IC50小于100nM的抑制率。特异性抑制和广谱性抑制在不同的应用中需要选择使用,以发挥各自的优势。如对于良性肿瘤或者肿瘤早期的患者而言,如能确定肿瘤细胞中的EGFR激酶类型,采用相应的特异性抑制是十分有利的,因为可以不影响其他EGFR激酶的正常生理功能;对于肿瘤晚期或长期治疗仍旧复发的患者而言,由于体内肿瘤细胞可能分化成多种耐药株了,因此采用广谱性抑制是非常有利的。
也优选本发明第四或第五方面的应用中,抑制是不可逆抑制。
在第六方面,本发明提供了本发明第一方面的化合物或其互变异构体、立体异构体、溶剂化物、前药或药学上可接受的盐的制备方法,其是化学合成方法。
优选本发明第六方面的方法如本发明实施例所述。
本发明取得的有益效果在于:提供新的含吲哚的喹唑啉类化合物,具有优异的抑制EGFR、HER2、HER3和/或HER4过度表达或异常激活的细胞增殖效果以及优异的特异性或广谱性抑制EGFR激酶的效果,对于耐药突变株的抑制效果也很好,而且抑制是不可逆的,从而可以高效地治疗肿瘤。
为了便于理解,以下将通过具体的附图和实施例对本发明进行详细地描述。需要特别指出的是,具体实例和附图仅是为了说明,并不构成对本发明范围的限制。显然本领域的普通技术人员可以根据本文说明,在本发明的范围内对本发明做出各种各样的修正和改变,这些修正和改变也纳入本发明的范围内。另外,本发明引用了公开文献,这些文献也是为了更清楚地描述本发明,它们的全文内容均纳入本发明进行参考,就好像它们的全文已经在本发明说明书中重复叙述过一样。
附图说明
图1本发明的含吲哚的喹唑啉类化合物对EGFR激酶的抑制率。
图2本发明的含吲哚的喹唑啉类化合物对EGFR-L858R、EGFR-T790M、EGFR-L858R/T790M等激酶的抑制活性(以IC50表示,单位:nM)。
图3本发明的含吲哚的喹唑啉类化合物在细胞内抗增殖的作用。
图4化合物R14和R15在细胞内对EGFR及其下游信号通路AKT、ERK的抑制作用,其中上图是针对HCC827细胞,下图是针对H1975细胞。
图5化合物R14、R15和R1对EGFR对EGFR磷酸化的不可逆抑制方式的验证。
具体实施方式
通过以下实施例对本发明作进一步详细说明,但不应理解为限定本发明的范围。
实施例1制备N4-(1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R1)
将2-氨基-5-硝基苄腈(化合物1,4.89g,30mmol),N,N-二甲基甲酰胺二甲缩醛(DMF-DMA,5.36g,45mmol)溶于甲苯(50ml)中,115℃加热回流,直至薄层层析显示反应完全。反应结束后旋干溶剂,固体用乙酸乙酯-正己烷体系洗数次,过滤,得黄色产物固体产物2,产率:89.7%。
在50ml圆底烧瓶中加入1.65g(7.56mmol)的中间体2,10ml乙酸,115℃加热回流。数分钟后加入等量的5-氨基吲哚(1.0g,7.56mmol),继续加热搅拌数小时,TLC监测至反应结束。随后向反应体系中加入饱和NaHCO3或NaOH调PH至中性,加入乙酸乙酯萃取3次,有机层水洗,NaCl洗,MgSO4干燥,合并有机层,旋干,得到2.25g黄色的硝基喹唑啉中间体3,产率:97.47%。
将化合物3(1100mg,2mmol),Fe粉(1.12g,20mmol,10equiv)加入乙醇(15ml)和冰醋酸(2ml)中,78℃加热回流1h,TLC监测。反应结束后,硅藻土过滤,甲醇洗沉淀至无色,旋干溶剂。固体随后加乙酸乙酯溶解,超声数分钟,NaHCO3调PH至7-8,加入乙酸乙酯萃取3次,有机层水洗,NaCl洗,MgSO4干燥。合并有机层,旋干,干燥后得粗品。后经柱层析纯化,得到黄色固体粉末1.03g,产率51.9%。1HNMR(600MHz,DMSO-d6)δ(ppm):11.048(s,1H,-NH),9.237(s,1H,-NH),8.216(s,1H,N=CH-N),7.927(s,1H,Ar-H),7.485(d,J=9HZ,Ar-H),7.381-7.385(m,1H,Ar-H),7.373-7.381(m,2H,Ar-H),7.323-7.332(m,1H,Ar-H),7.207(d,J=8.4HZ,Ar-H),6.410(s,1H,Ar-H),5.477(s,2H,-NH2).ESI-MS m/z:275.8(M+H)+,calcdfor C16H13N5:275.31.
实施例2制备N4-(1-甲基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R2)
将5-硝基吲哚(972mg,6mmol),K2CO3(1.66g,7.2mmol)溶于乙腈(20ml)中,于80℃加热回流数小时,TLC监测至反应结束。随后旋干溶剂,固体用乙酸乙酯溶解后,加入饱和NH4Cl溶液,萃取。合并有机层,旋干得粗品。最后过柱纯化得中间产物1-甲基-5-硝基-1H-吲哚769mg。产率47.5%。
将1-甲基-5-硝基-1H-吲哚(270mg,1mmol),Fe粉(1.12g,20mmol,10equiv)加入乙醇(15ml)和冰醋酸(2ml)中,78℃加热回流1h,TLC监测。反应结束后,硅藻土过滤,乙醇洗沉淀至无色,旋干溶剂乙醇。固体随后加乙酸乙酯溶解,超声数分钟,萃取,饱和NaHCO3洗,水洗,NaCl洗,饱和MgSO4干燥。有机层旋干,干燥,粗品经柱层析纯化得230mg黄色产物1-甲基-5-氨基-1H-吲哚,产率95.8%。
1-甲基-5-氨基-1H-吲哚后与中间体2在乙酸中加热成环,随后经Fe粉还原为目标产物R2,其制备方法类似实施例1,不同的是1-甲基-5-氨基-1H-吲哚代替5-氨基吲哚,在此不做详细描述。1HNMR(600MHz,DMSO-d6)δ(ppm):9.253(s,1H,-NH),8.243(s,1H,N=CH-N),7.976(s,1H,Ar-H),7.490-7.505(m,1H,Ar-H),7.443-7.461(m,1H,Ar-H),7.394-7.408(m,2H,Ar-H),7.300(s,1H,Ar-H),7.226-7.207(m,1H,Ar-H),6.411-6.415(m,1H,Ar-H),5.488(s,2H,-NH2),3.790(s,3H,-CH3).ESI-MS m/z:289.8(M+H)+,calcd for C17H15N5:289.33.
实施例3制备N4-(1-丙基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R3)
制备方法类似实施例2,不同的是将溴丙烷代替碘甲烷,终产物为标题化合物,R3。1HNMR(600MHz,DMSO-d6)δ(ppm):9.232(s,1H,-NH),8.223(s,1H,Ar-H),7.943(s,1H,Ar-H),7.493-7.350(m,4H,Ar-H),7.214(d,J=2.4Hz,1H,indole-H),7.200(d,J=2.4,1H,indole-H),6.412(s,1H,Ar-H),5.477(s,2H,-NH2),4.119-4.142(m,2H,-CH2-),1761-1.809(m,2H,-CH2-),0.838-0.863(m,3H,-CH3).ESI-MS m/z:318.1(M+H)+,340.0(M+Na)+,calcdfor C19H19N5:317.39.
实施例4制备N4-(1-烯丙基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R4)
制备方法类似实施例2,不同的是将烯丙基溴代替碘甲烷,终产物为标题化合物,R4。1HNMR(600MHz,DMSO-d6)δ(ppm):9.239(s,1H,-NH),8.227(s,1H,Ar-H),7.965(s,1H,Ar-H),7.486(d,J=9.1Hz,Ar-H),7.327-7.425(m,4H,Ar-H),7.199-7.217(m,1H,Ar-H),6.450(s,1H,Ar-H),5.999-6.044(m,1H,CH2=CH-CH2-),5.480(s,2H,-NH2),5.168-5.21(m,2H,CH2=CH-CH2-),4.821(s,J=5.4Hz,2H,CH2=CH-CH2-).ESI-MS m/z:316.0(M+H)+,338.1(M+Na)+,calcd for C19H17N5:315.37.
实施例5制备N4-(1-(3-氟苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R5)
制备方法类似实施例2,不同的是将3-氟苄溴代替碘甲烷,终产物为标题化合物,R5。1HNMR(600MHz,DMSO-d6)δ(ppm):9.250(s,1H,-NH),8.228(s,1H,Ar-H),8.181(s,1H,Ar-H),7.485-7.521(m,2H,Ar-H),7.355-7.425(m,4H,Ar-H),7.207-7.220(m,1H,Ar-H),7.008-7.096(m,3H,Ar-H),6.504(s,1H,Ar-H),5.594(s,2H,-NH2),5.448(s,2H,-CH2).ESI-MSm/z:384.0(M+H)+,calcd for C23H18FN5:383.42.
实施例6制备N4-(1-(3-氯苄基)-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R6)
制备方法类似实施例2,不同的是将3-氯苄溴代替碘甲烷,终产物为标题化合物,R6。1HNMR(600MHz,DMSO-d6)δ(ppm):9.254(s,1H,-NH),8.236(s,1H,Ar-H),7.985(s,1H,Ar-H),7.490-7.523(m,2H,Ar-H),7.398-7.443(m,2H,Ar-H),7.308-7.375(m,3H,Ar-H),7.256(s,1H,Ar-H),7.219(d,1H,J=8.4Hz,Ar-H),7.159(d,1H,J=7.2Hz,Ar-H),6.508(s,1H,Ar-H),5.497(s,2H,-NH2),5.441(s,2H,-CH2).ESI-MS m/z:400.0(M+H)+,calcd forC23H18ClN5:399.88.
实施例7制备N4-(2-甲基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R7)
制备方法类似实施例1,不同的是将2-甲基-5-氨基吲哚代替5-氨基吲哚,终产物为标题化合物,R7。1HNMR(600MHz,DMSO-d6)δ(ppm):10.831(s,1H,-NH),9.168(s,1H,-NH),8.213(s,1H,Ar-H),7.773(s,1H,Ar-H),7.477(d,J=9Hz,1H,Ar-H),7.374(s,1H,Ar-H),7.293-7.190(m,3H,Ar-H),6.105(s,1H,Ar-H),5.456(s,2H,-NH2),2.381(s,3H,-CH3).ESI-MSm/z:289.8(M+H)+,calcd for C17H15N5:289.33.
实施例8制备N4-(2-叔丁基-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R8)
制备方法类似实施例1,不同的是将2-叔丁基-5-氨基吲哚代替5-氨基吲哚,终产物为标题化合物,R8。1HNMR(600MHz,DMSO-d6)δ(ppm):10.806(s,1H,-NH),9.185(s,1H,Ar-H),8.196(s,1H,Ar-H),7.769(s,1H,Ar-H),7.472(d,J=8.4Hz,1H,Ar-H),7.379(s,1H,Ar-H),7.301(d,J=9Hz,1H,Ar-H),7.261(d,J=8.4Hz,1H,Ar-H),7.195(d,J=9Hz,1H,Ar-H),6.108(s,1H,-NH),5.451(s,2H,-NH2),1.357(s,9H,-CH3).ESI-MS m/z:332.0(M+H)+,calcdfor C20H21N5:331.41.
实施例9制备5-((6-氨基喹唑啉-4-芳基)氨基)-1H-吲哚-2-羧酸乙酯(化合物R9)
制备方法类似实施例1,不同的是将5-氨基吲哚-2-羧酸乙酯代替5-氨基吲哚,终产物为标题化合物,R9。1HNMR(600MHz,DMSO-d6)δ(ppm):11.830(s,1H,-NH),9.309(s,1H,-NH),8.253(s,1H,N=CH-N),8.076(s,1H,Ar-H),7.584-7.601(m,1H,Ar-H),7.498(d,1H,J=9Hz,Ar-H),7.435(d,1H,J=9Hz,Ar-H),7.375(s,1H,Ar-H),7.208-7.227(m,1H,Ar-H),7.149(s,1H,Ar-H),5.508(s,2H,-NH2),4.329-4.364(m,2H,-CH2),1.338-1.362(m,3H,-CH3).ESI-MS m/z:347.9(M+H)+,calcd for C19H17N5O2:347.37.
实施例10制备5-((6-氨基喹唑啉-4-芳基)氨基)-1H-吲哚-2-羧酸(化合物R10)
中间体2与5-氨基吲哚-2-羧酸乙酯成环生成中间体4后,将4(400mg,1.06mmol)溶解于乙醇(10ml)中,40℃加热搅拌,分3次滴加2ml的20%NaOH溶液,搅拌过夜。TLC检测至反应结束。旋干溶剂乙醇,加入50ml水溶解,随后缓慢滴加稀HCl至PH=3-4,发现有大量红色沉淀析出,过滤,干燥,得350mg中间产物5,产率94.5%。中间产物5经实施例1所述的Fe粉还原法得到标题化合物,R10。1HNMR(600MHz,DMSO-d6)δ(ppm):11.708(s,1H,-OH),9.344(s,1H,-NH),8.262(s,1H,N=CH-N),8.068(s,1H,Ar-H),7.548-7.561(m,1H,Ar-H),7.500(d,1H,J=8.4Hz,Ar-H),7.416(d,1H,J=9Hz,Ar-H),7.381(s,1H,Ar-H),7.212-7.227(m,1H,Ar-H),7.087(s,1H,Ar-H),5.522(s,2H,-NH2).ESI-MS m/z:319.9(M+H)+,calcdforC17H13N5O2:319.32.
实施例11制备5-((6-氨基喹唑啉-4-芳基)氨基)-N-丙基-1H-吲哚-2-酰胺(化合物R11)
中间产物5经实施例10所得,将化合物5(150mg,0.43mmol)溶解于DMF(10ml)中,加入EDC.HCl(124mg,0.64mmol),HOBt(70mg,0.52mmol)以及三乙胺数滴,室温搅拌。30min后加入正丙胺(50mg,0.86mmol)。室温搅拌过夜。反应结束后,加入乙酸乙酯萃取,大量饱和食盐水洗掉DMF,合并有机相后旋干溶剂,得中间产物6。产率86%。
中间产物6经实施例1所述的Fe粉还原法得到标题化合物,R11。1H NMR(600MHz,DMSO-d6)δ(ppm):11.487(s,1H,-NH),9.265(s,1H,Ar-H),8.442(d,1H,Ar-H),8.238(d,1H,Ar-H),8.006(s,1H,indole-NH),7.502(s,2H,-NH),7.401(d,1H,J=9,Ar-H),7.327(d,1H,J=1.2,-H),7.269(s,1H,indole-H),7.124(s,1H,-H),7.007(s,1H,indole-H),5.490(s,1H,-NH),3.253-3.294(m,2H,indole-CH2),1.561-1.584(m,2H,-CH2),0.908-0.953(m,3H,-CH3).ESI-MSm/z:360.9(M+H)+,calcd for C20H20N6O:360.41.
实施例12制备5-((6-氨基喹唑啉-4-芳基)氨基)-N-叔丁基-1H-吲哚-2-酰胺(化合物R12)
制备方法类似实施例11,不同的是将叔丁胺代替正丙胺,终产物为标题化合物,R12。1HNMR(600MHz,DMSO-d6)δ(ppm):11.415(s,1H,-NH),9.266(s,1H,Ar-H),8.248(d,1H,J=8.4,Ar-H),7.963(s,1H,-NH),7.679(s,1H,Ar-H),7.501(d,2H,J=4.8,indole-H),7.401(s,1H,Ar-H),7.38(d,1H,J=7.2,indole-H),7.219(s,2H,-NH2),7.008(s,1H,indole-H),5.490(s,1H,-NH),1.481(s,9H,-CH3).ESI-MS m/z:374.9(M+H)+,calcd forC21H22N6O:374.44.
实施例13制备N4-(3-溴-1H-吲哚-5-芳基)喹唑啉-4,6-二胺(化合物R13)
中间产物3经实施例1所述的方法得到。将化合物3(1.5g,5mmol),N-溴代丁二酰亚胺(1g,6mmol)溶解于DMF(10ml)中,加入少量过氧化二苯甲酰,60℃加热回流,过夜。TLC检测至反应结束后,加入水,析出固体,抽滤,少量醇洗、水洗得粗品,后经柱层析纯化得到中间产物7。1HNMR(600MHz,DMSO-d6)δ(ppm):11.532(s,1H,-NH),10.508(s,1H,-NH),9.689(s,1H,N=CH-N),8.662(s,1H,Ar-H),8.662(s,1H,Ar-H),8.548(d,J=9HZ,Ar-H),7.910(d,J=9HZ,Ar-H),7.833(s,1H,proline-H),7.592(s,1H,Ar-H),7.618(d,J=8.4HZ,Ar-H),7.481(d,J=8.4HZ,Ar-H).ESI-MS m/z:383.9(M+H)+,calcd for C16H10BrN5O2:384.19.
中间产物7经实施例1所述的Fe粉还原法得到标题化合物,R13。1H NMR(600MHz,DMSO-d6)δ(ppm):11.410(s,1H,-NH),9.324(s,1H,N=CH-N),8.260(s,1H,Ar-H),7.852(s,1H,Ar-H),7.580(d,J=9.0Hz,Ar-H),7.529(s,1H,Ar-H),7.500(d,J=9.0Hz,Ar-H),7.410(d,J=9.0Hz,1H),7.394(s,1H,Ar-H),7.222(d,J=9.0Hz,1H),5.502(s,2H,-NH2).ESI-MSm/z:354.6(M+H)+,calcd for C16H12BrN5:354.20.
实施例14制备N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺(化合物R14)
冰浴条件下将化合物R1(550mg,2mmol)溶解于四氢呋喃(10ml)中,加入数滴三乙胺,-20℃条件下缓慢滴加丙烯酰氯(2.2mmol)的THF溶液,继续反应,TLC检测。反应结束后加入饱和的NH4Cl溶液淬灭,随后加入乙酸乙酯萃取3次,有机层水洗,NaCl洗,MgSO4干燥。合并有机层,旋干,干燥后得粗品。后经柱层析纯化,得到黄色固体粉末300mg,产率45.5%。1H NMR(600MHz,DMSO-d6)δ(ppm):11.104(s,1H,-NH),10.883(s,1H,-CONH),9.807(s,1H,-NH),8.761(s,1H),8.410(s,1H),7.922(s,1H),7.888(d,J=9.0Hz,1H),7.732(d,J=9.0Hz,1H),7.539(d,J=3.0Hz,1H),7.443(d,J=8.4Hz,1H),7.379(d,J=9Hz,1H),7.354(d,J=7.8Hz,1H),7.020-7.076(m,1H),6.335(d,J=16.8Hz,1H),5.826(d,J=10.2Hz,1H).ESI-MS m/z:330.0(M+H)+,calcd for C19H15N5O:329.36.
实施例15制备N-(4-((1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰氯(化合物R15)
冰浴条件下将化合物R1(550mg,2mmol)溶解于四氢呋喃(10ml)中,缓慢滴加过量的3-氯丙酰氯(10mmol),继续室温搅拌,TLC检测。反应结束后加入饱和的NH4Cl溶液淬灭,随后加入乙酸乙酯萃取3次,有机层水洗,NaCl洗,MgSO4干燥。合并有机层,旋干,干燥后得粗品。后经柱层析纯化,得到黄色固体粉末410mg,产率62.0%。1H NMR(600MHz,DMSO-d6)δ(ppm):11.266(s,1H,-NH),10.892(s,1H,-CONH),8.761(s,1H),8.410(s,1H),7.922(s,1H),7.888(d,J=9.0Hz,1H),7.732(d,J=9.0Hz,1H),7.539(d,J=3.0Hz,1H),7.443(d,J=8.4Hz,1H),7.379(d,J=9Hz,1H),7.354(d,J=7.8Hz,1H),3.925-3.952(m,2H,-CH2),2.906-2.951(m,2H,-CH2).ESI-MS m/z:366.1(M+H)+,calcd for C19H16ClN5O:365.82.
实施例16制备N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺(化合物R16)
制备方法类似实施例14,不同的是将R5代替R1与丙烯酰氯反应,终产物为标题化合物,R16。1H MR(600MHz,DMSO-d6)δ(ppm):10.632(s,1H,-CONH),9.772(s,1H,-NH),8.761(s,1H),8.412(s,1H),7.921(s,1H),7.888(d,J=9.0Hz,1H),7.732(d,J=9.0Hz,1H),7.539(d,J=3.0Hz,1H),7.443(d,J=8.4Hz,1H),7.380(d,J=9Hz,1H),7.354(d,J=7.8Hz,1H),7.095(d,J=7.2Hz,1H),7.046(d,J=8.4Hz,1H),7.020-7.076(m,1H),6.550(s,1H),5.459(s,2H,-CH2),3.925-3.952(m,2H,-CH2),2.906-2.951(m,2H,-CH2).ESI-MSm/z:474.6(M+H)+,calcd for C26H21ClFN5O:473.93.
实施例17制备N-(4-((1-(3-氟苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺(化合物R17)
制备方法类似实施例15,不同的是将R5代替R1与3-氯丙酰氯反应,终产物为标题化合物,R17。1H NMR(600MHz,DMSO-d6)δ(ppm):10.632(s,1H,-CONH),9.772(s,1H,-NH),8.761(s,1H),8.412(s,1H),7.921(s,1H),7.888(d,J=9.0Hz,1H),7.732(d,J=9.0Hz,1H),7.539(d,J=3.0Hz,1H),7.443(d,J=8.4Hz,1H),7.380(d,J=9Hz,1H),7.354(d,J=7.8Hz,1H),7.095(d,J=7.2Hz,1H),7.046(d,J=8.4Hz,1H),7.020-7.076(m,1H),6.550(s,1H),5.459(s,2H,-CH2),3.925-3.952(m,2H,-CH2),2.906-2.951(m,2H,-CH2).ESI-MSm/z:474.6(M+H)+,calcd for C26H21ClFN5O:473.93.
实施例18制备N-(4-((1-(3-氯苄基)-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)3-氯丙酰胺(化合物R18)
制备方法类似实施例15,不同的是将R6代替R1与3-氯丙酰氯反应,终产物为标题化合物,R18。1H NMR(600MHz,DMSO-d6)δ(ppm):10.372(s,1H,-CONH),9.772(s,1H,-NH),8.761(s,1H),8.412(s,1H),7.921(s,1H),7.888(d,J=9.0Hz,1H),7.732(d,J=9.0Hz,1H),7.539(d,J=3.0Hz,1H),7.443(d,J=8.4Hz,1H),7.380(d,J=9Hz,1H),7.354(d,J=7.8Hz,1H),7.095(d,J=7.2Hz,1H),7.046(d,J=8.4Hz,1H),7.020-7.076(m,1H),6.552(s,1H),5.459(s,2H,-CH2),3.925-3.950(m,2H,-CH2),2.906-2.953(m,2H,-CH2).ESI-MSm/z:491.0(M+H)+,calcd for C26H21Cl2N5O:490.38.
实施例19制备N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)丙烯酰胺(化合物R19)
制备方法类似实施例14,不同的是将R13代替R1与丙烯酰氯反应,终产物为标题化合物,R19。1H NMR(600MHz,DMSO-d6)δ(ppm):11.470(s,1H,-NH),10.408(s,1H,-NHCO),9.930(s,1H,-NH),8.735(s,1H,N=CH-N),8.464(s,1H,Ar-H),7.884(d,J=9Hz,1H),7.800(s,1H,Ar-H),7.758(d,J=9Hz,1H),7.577(d,J=8.4Hz,1H),7.556(s,1H,Ar-H),7.443(d,J=8.4Hz,1H),5.835(d,J=11.4Hz,CH2=CH),6.347(d,J=16.8Hz,CH2=CH),6.516-6.561(m,1H,CH2=CH).ESI-MS m/z:408.6(M+H)+,calcd for C19H14BrN5O:408.25.
实施例20制备N-(4-((3-溴-1H-吲哚-5-芳基)氨基)喹唑啉-6-芳基)-3-氯丙酰胺(化合物R20)
制备方法类似实施例15,不同的是将R13代替R1与3-氯丙酰氯反应,终产物为标题化合物,R20。1H NMR(600MHz,DMSO-d6)δ(ppm):11.470(s,1H,-NH),10.408(s,1H,-NHCO),9.930(s,1H,-NH),8.735(s,1H,N=CH-N),8.464(s,1H,Ar-H),7.860(d,J=9Hz,1H),7.778(s,1H,Ar-H),7.748(d,J=9Hz,1H),7.551(d,J=8.4Hz,1H),7.557(s,1H,Ar-H),7.444(d,J=8.4Hz,1H),3.932-3.952(m,3H,-CH2-),2.916-2.937(m,3H,-CH2-).ESI-MS m/z:446.0(M+H)+,calcd for C19H15BrClN5O:444.71.
实施例21本发明的化合物对不同EGFR激酶的抑制活性测试
实验采用方法为Caliper Mobility Shift Assay,该方法是以微流体芯片技术的迁移率检测技术为核心的检测平台。实验步骤:配置1.25x激酶反应缓冲液(62.5mmol/LHEPES,pH7.5;0.001875%Brij-35;12.5mmol/LMgCl2;2.5mM DTT)和激酶反应终止液(100mmol/L HEPES,pH7.5;0.015%Brij-35;0.2%Coating Reagent#3);在5μl的5x浓度的化合物溶液中(用DMSO溶解,用水稀释10倍)加入10μl的2.5x的EGFR激酶溶液(在1.25x激酶反应缓冲液中加激酶),室温孵育10min后再加入10μl的2.5x底物肽溶液(在1.25x激酶反应缓冲液中加FAM标记肽和ATP),在28℃下反应特定的时间后加入25μL激酶反应终止液。在Caliper上测试收集数据,对激酶活性的抑制率=(max-conversion)/(max-min)*100。“max”为未加化合物的DMSO对照,“min”为低对照。测定IC50时每种样品设10个稀释度各2个复孔,3次重复。
通过上述方法分别在0.1,1,10,100,1000,10000等6个浓度下测定20个含吲哚的喹唑啉类化合物对野生型EGFR激酶的抑制活性,IC50结果见图1。
激酶选择性抑制测试:将R1、R5、R6、R13、R14、R15、R16、R17、R18、R19、R20按照依照上述激酶抑制活性测定方法,测定它们对EGFR敏感突变激酶EGFR-L858R及EGFR突变耐药激酶EGFR-T790M和EGFR-L858R/T790M等激酶的抑制活性,以表征部分抑制剂对EGFR突变株的抑制效果,IC50结果见图2。
激酶实验表明:化合物R1、R5、R6和R13对野生型的EGFR均具有很好的抑制活性,其IC50达到了nM水平;以此类结构改造得到的不可逆抑制剂R14、R15、R16、R17、R18、R19、R20不仅对野生型的EGFR激酶具有优秀的抑制活性,其对EGFR敏感突变的激酶EGFR-L858R也具有很强的抑制作用。另外,此类不可逆抑制还显示出不同程度的对EGFR耐药突变株EGFR-T790M及EGFR-L858R/T790M抑制作用,尤其是化合物R19和R20对两种激酶的抑制活性的IC50达到了nM的水平(实验数据见图2)。
实施例22测试本发明化合物对不同肿瘤细胞株的IC50值
实验采用MTT法,测试本发明化合物对不同肿瘤细胞株的IC50值。选用EGFR高表达的人非小细胞肺癌细胞HCC827和H1975(含EGFR-T790M耐药突变)细胞等进行增殖抑制活性测试。测定时以PBS为空白对照,DMSO为阴性对照,吉非替尼为阳性对照,待测化合物每种样品设6个浓度梯度,设置3个复孔,计算IC50值。实验结果见图3。
结果表明,大部分化合物对HCC827均具有较好抑制效果,如R1、R5、R13-R20都在μM水平抑制HCC827的增殖,活性基本与阳性药物吉非替尼相当。且本发明涉及的不可逆抑制剂R16、R18、R19和R20等可以显著性的抑制H1975的增殖,而阳性药对吉非替尼对于吉非替尼几乎无效,其IC50>50μM。
实施例23细胞水平上化合物的抗肿瘤活性验证
将化合物R14、R15和吉非替尼分别用DMSO配置成0.01,0.1和1μM浓度(或0.1,1和10μM)的溶液,用EGF联合上述不同浓度的活性化合物分别处理EGFR高表达的非小细胞肺癌细胞HCC827(敏感)和H1975(含T790M突变)细胞。同时,提取细胞总蛋白,利用Westernblotting检测细胞内EGF/EGFR信号通路中促增殖信号分子EGFR、ERK和AKT磷酸化水平的变化,检测三种化合物的抗肿瘤增殖活性。实验结果见图4。
结果显示,化合物R14、R15均具有较好的抗肿瘤增殖活性。在HCC827细胞中,R14在0.01μM的时候就能完全抑制EGFR的磷酸化,效果明显优于吉非替尼;而化合物R15也能达到与吉非替尼几乎相同的抑制效果。对于含有T790M突变的H1975细胞,吉非替尼在最高浓度10μM的时候抑制作用都不明显,但经我们改造的不可逆抑制剂R14和R15则显示出剂量依赖的方式抑制EGFR及下游AKT和ERK的磷酸化,效果明显优于吉非替尼。
实施例24细胞水平上不可逆抑制方式验证
一般而言,在药物与细胞作用一定时间后,吸掉培养基,分别在不同时间点收集细胞,裂解后提取总蛋白,利用Western Blot检测EGFR的磷酸化水平。可逆抑制剂对蛋白的磷酸化的抑制作用会在短时间内恢复;若8h后依然能维持80%或者以上的抑制率则可认为该类抑制剂为不可逆抑制剂。
将化合物R1、R14、R15预处理人非小细胞肺癌HCC827细胞株1h后,吸掉培养基,加入20ng/mL的EGF刺激细胞,分别在30min,1h,2h,4h,8h和24h时间点分别收集细胞,裂解后提取总蛋白,利用Western Blot检测EGFR的磷酸化水平。图5的结果显示,R1在1h的时候几乎完全抑制EGFR的磷酸化,但是4h后其磷酸化水平几乎完全恢复,由此我们可推断R1为可逆抑制剂。相比较而言,化合物R14和R15则在8h后仍然维持很高的EGFR磷酸化抑制活性,甚至12h都未完全恢复。由此可见R14、R15以不可逆抑制的方式抑制EGFR的磷酸化。
Claims (2)
1.一种含吲哚的喹唑啉类化合物或其互变异构体、立体异构体、或药学上可接受的盐在制备用于特异性或广谱性抑制EGFR 激酶的药物中的应用,其特征在于,所述化合物选自:
N4-(3- 溴-1H- 吲哚-5-) 喹唑啉-4,6- 二胺(R13) ;
所述药物用于抑制敏感突变激酶EGFR-L858R、突变耐药激酶EGFR-T790M和EGFR-L858R/T790M;
或者所述化合物选自N-(4-((3- 溴-1H- 吲哚-5-) 氨基) 喹唑啉-6-) 丙烯酰胺(R19) ;
所述药物用于抑制突变耐药激酶EGFR-T790M和EGFR-L858R/T790M。
2.根据权利要求1 所述的应用,其特征在于,所述的药物包含权利要求1 所述的化合物或其互变异构体、立体异构体或药学上可接受的盐,以及药学上可接受的辅料。
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Address after: 325035 Zhejiang province Chashan Wenzhou Higher Education Park of Wenzhou Medical College Co-patentee after: WENZHOU GUANGCHENG BIOTECHNOLOGY Co.,Ltd. Patentee after: WENZHOU MEDICAL University Address before: 325035 Zhejiang province Chashan Wenzhou Higher Education Park of Wenzhou Medical College Co-patentee before: WENZHOU GUANGCHENG BIOTECHNOLOGY Co.,Ltd. Patentee before: Wenzhou Medical College |
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Granted publication date: 20171128 |